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Prepublished online as a Blood First Edition Paper on May 15, 2003; DOI 10.1182/blood-2003-01-0166.
Submitted January 23, 2003
Accepted April 30, 2003
Regulation of plasminogen activation: a role for melanotransferrin (p97) in cell migration
Michel Demeule, Yanick Bertrand, Jonathan Michaud-Levesque, Julie Jodoin, Yanneve Rolland, Reinhard Gabathuler, and Richard Beliveau*
Hemato-Oncology Center, Ste-Justine Hospital-UQAM, Montreal, PQ, Canada
Biomarin Pharmaceutical Inc., Novato, CA, USA
* Corresponding author; email: oncomol{at}nobel.si.uqam.ca.
We have recently reported that human recombinant melanotransferrin (p97) presents a high transport rate across the blood-brain barrier which might involve the low-density lipoprotein related protein (LRP) (Demeule et al., 2002). We now report new interactions between p97 and another LRP ligand, the urokinase plasminogen activator (uPA) complex. By using biospecific interaction analysis, both pro-uPA and plasminogen are shown to interact with immobilized p97. Moreover, the activation of plasminogen by pro-uPA is increased by soluble p97. Because the uPA system plays a crucial role in cell migration, both in cancer and angiogenesis, we also measured the impact of both endogenous membrane-bound and exogenous p97 on cell migration. The mAb L235 (which recognizes a conformational epitope on p97) inhibited the migration of human microvascular endothelial cells (HMEC-1) and of human melanoma SK-MEL28 cells, indicating that endogenous membrane-bound p97 could be associated with this process. In addition, low concentrations of exogenous p97 (10 and 100 nM) inhibited HMEC-1 and SK-MEL28 cell migration by more than 50%. These results indicate that membrane-bound and soluble p97 affect the migration capacity of endothelial and melanoma cells and suggest that p97 could be involved in the regulation of plasminogen activation by interacting with pro-uPA and plasminogen.
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